Cited by 117Chronic Myeloid Leukemia TreatmentsDNA Repair MechanismsCancer-related Molecular Pathways

BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint

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Dierov, Jamil, Dierova, Raia, Carroll, Martin·2004·Cancer Cell

Abstract

Chronic myelogeneous leukemia (CML) is a two-stage disease associated with expression of the BCR/ABL tyrosine kinase protein. However, whether BCR/ABL expression directly causes blast crisis, and if so by what mechanism, is unknown. We have found that BCR/ABL translocates from the cytoplasm to the nucleus after genotoxic stress. Furthermore, BCR/ABL increases DNA double-strand damage after etoposide treatment and leads to a defect in an intra-S phase checkpoint, causing a radioresistant DNA synthesis (RDS) phenotype. In the nucleus, BCR/ABL associates with the ataxia-telangiectasia and rad 3-related protein (ATR) and disrupts ATR-dependent signal transduction. Overexpression of ATR in a BCR/ABL-expressing cell line corrects the DNA damage phenotype. These results demonstrate a nuclear role for BCR/ABL in altering the cellular response to DNA damage.

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Crossref · 10.1016/s1535-6108(04)00056-x

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Authors
Dierov, J., Dierova, R., & Carroll, M.
Affiliations
University of Pennsylvania (US)
Corresponding author
Carroll, Martin
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2004-03
Volume
5
Issue
3
Pages
275-285
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2035713316
Cited by
117
References
40
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 4 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 2 · 2012: 9
FWCI
7.97
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
BCR-ABL, chronic myeloid leukemia, nuclear translocation, ATR, S-phase checkpoint, DNA damage response, radioresistant DNA synthesis, etoposide, DNA double-strand breaks, blast crisis, tyrosine kinase
MeSH terms
Cell Nucleus, Cells, Cultured, Cytoplasm, DNA Damage, DNA Topoisomerases, Type II, DNA Repair, Enzyme Inhibitors, Etoposide, Humans, Signal Transduction, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Fusion Proteins, bcr-abl, S Phase, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Protein Transport, Ataxia Telangiectasia Mutated Proteins

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